Hepatitis B virus (HBV) is a major cause of morbidity and mortality, worldwide. About 350 million people suffer from chronic HBV and about 600,000 die from its sequellae annually. HBV is an enveloped virus with an icosahedral core that also functions as a metabolic compartment. Indeed, the core protein plays pleiotropic roles in many elements of HBV replication. To accomplish multiple functions we hypothesize a complex allosteric regulation of the protein and the assembled core. We will study assembly of empty cores and correlate that with assembly of cores on nucleic acid substrates. We will examine assembly of cores on nucleic acid substrates and correlate that with reverse transcription. Our preliminary data indicates that the core plays an active role in reverse transcription; it is much more than a passive container. We will correlate the synergism between core structure and reverse transcription with intracellular localization of core. By emphasizing the structural basis f these correlations, we will define the mechanisms relating assembly, reverse transcription of viral RNA, and core trafficking within a cell. In the last few years, the HBV core protein has emerged as a target for antiviral therapeutics. The studies described in our proposal will serve as a basis for defining molecular mechanisms of such antiviral molecules.